The pharmaceutical antibiotic composition comprising ceftolozane and tazobactam in a 2:1 weight ratio of ceftolozane active to tazobactam acid (“CXA-201”) displays potent antibacterial activity, including antibiotic activity against infections caused by many Gram-negative pathogens such as Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), Klebsiella pneumonia (K. pneumonia). In particular, CXA-201 is a pharmaceutical composition being developed for intravenous administration for the treatment of complicated intra-abdominal infections and/or complicated urinary tract infections, and is being evaluated for treatment of pneumonia.
Ceftolozane is a cephalosporin antibacterial agent, also referred to as CXA-101, FR264205, or by chemical names such as (6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazol-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, and 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylate. The antibacterial activity of ceftolozane is believed to result from its interaction with penicillin binding proteins (PBPs) to inhibit the biosynthesis of the bacterial cell wall which acts to stop bacterial replication. Ceftolozane sulfate is a pharmaceutically acceptable ceftolozane salt of formula (I) that can be formulated for intravenous administration or infusion.

In CXA-201, ceftolozane is combined with the β-lactamase inhibitor (“BLI”) tazobactam. Tazobactam is a BLI against Class A and some Class C β-lactamases, with well-established in vitro and in vivo efficacy in combination with active β-lactam antibiotics. Tazobactam can be combined with ceftolozane as a lyophilized composition obtained by lyophilizing a solution of water, a sodium containing base (e.g., sodium bicarbonate) and the tazobactam acid form of formula (II).

Pharmaceutical compositions comprising one or more drug substances can be prepared by lyophilization of a solution containing the drug substance(s). Lyophilization is a process of freeze-drying in which water is sublimed from a frozen solution of one or more solutes. Specific methods of lyophilization are described in Remington's Pharmaceutical Sciences, Chapter 84, page 1565, Eighteenth Edition, A. R. Gennaro, (Mack Publishing Co., Easton, Pa., 1990). The formulation of pharmaceutical compositions can be selected to minimize decomposition of the constituent drug substances and to produce a composition that is stable under a variety of storage conditions.
As disclosed herein, compositions formed by lyophilizing ceftolozane and tazobactam demonstrated an increase in total ceftolozane related substance impurities over time of about 31-36% after 3 months at 25 degrees C. (e.g., see data tables in FIGS. 6A and 9A) and about 200-264% after 3 months at 40 degrees C. (e.g., see data tables in FIGS. 6B and 9B). As a result of increasing ceftolozane related substance impurities over time, the amount of ceftolozane in a pharmaceutical composition can decrease prior to placement of a ceftolozane composition within a unit dosage form container. Unit dosage forms that fail to comply with applicable specifications over time, such as the ceftolozane purity or increased amounts of ceftolozane related substances over time, cannot be used to treat patients and must be safely and appropriately discarded. This points to a potential benefit of unit dosage forms of pharmaceutical compositions (e.g., CXA-201 compositions) with reduced levels of ceftolozane related substance impurities for longer periods of time after manufacturing, and methods of manufacturing these unit dosage forms (e.g., to extend the shelf-life of the unit dosage form product).